Hypercalcaemia in selected lympho- and myeloproliferative malignancies – – pathophysiology, diagnostic approach and treatment
More details
Hide details
Katedra i Klinika Hematologii i Transplantacji Szpiku Wydziału Lekarskiego w Katowicach Śląskiego Uniwersytetu Medycznego w Katowicach
Koło Naukowe Studenckiego Towarzystwa Naukowego przy Katedrze i Klinice Hematologii i Transplantacji Szpiku Śląskiego Uniwersytetu Medycznego w Katowicach
Dariusz Kata   

Katedra i Klinika Hematologii i Transplantacji Szpiku Wydziału Lekarskiego w Katowicach Śląskiego Uniwersytetu Medycznego w Katowicach, ul. Dąbrowskiego 25, 40-032 Katowice, tel. 32 259 13 15
Ann. Acad. Med. Siles. 2015;69:14–25
Hypercalcaemia is a serious metabolic complication of neoplastic diseases. Among hematological malignancies, hypercalcemia is particularly associated with multiple myeloma, it has rarely been reported in patients with non-Hodgkin's and Hodgkin's lymphomas, or in cases of acute and chronic myeloproliferative diseases. The pathogenetic mechanism of hypercalcaemia is complex. A key process is an increase in osteoclast activity as a result of disturbances in the NF-kB ligand (RANKL) receptor activator system, its receptor (RANK) and osteoprotegerin. In addition, many other humoral factors were identified – hormones (for example the parathyroid hormone related peptide), vitamin D active metabolites, cytokines/chemokines and their receptors, and also transcription factors which are responsible for bone resorption and the development of hypercalcaemia in cases of particular neoplasms. This article presents the current opinions on the pathogenesis, symptomatology and current treatment methods of hypercalcaemia. Besides that, new experimental methods of therapy are described.
Kokot F. Gospodarka wodno-elektrolitowa i kwasowo-zasadowa w stanach fizjologii i patologii, Wydawnictwo Lekarskie PZWL, Warszawa 2005, s. 129.
Parfitt A.M. Equilibrium and disequilibrium hypercalcaemia: new light on an old concept. Metabolic Bone Dis. Rel. Res. 1979; 1: 279.
Mundy G.R., Martin T.J. The hypercalcemia of malignancy: pathogenesis and 4. management. Metabolism 1982; 31: 1247–1277.
Clines G.A., Guise T.A. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr. Relat. Cancer 2005; 12: 549–583.
Tashjian A.H Jr, Wright D.R, Ivey J.L., Pont A. Calcitonin binding sites in bone: relationships to biological response and "escape". Recent Prog. Horm. Res. 1978; 34: 285–334.
Gellert R. Hipo- i hiperkalcemia – patogeneza i problemy terapeutyczne. Forum Nefrol. 2011; 4: 373–382.
Ralston S.H., Coleman R., Fraser W.D. i wsp. Medical management of hypercalcemia. Calcif. Tissue Int. 2004; 74: 1–11.
Daisley H., Charles W.P. Hypercalcemia assosiated with Adult Cell Leukemia/Lymphoma. J. Natl. Med. Assoc. 1996; 88: 263–312.
Carroll M.F., Schade D.S. A practical approach to hypercalcemia. Am. Fam. Phys. 2003; 67: 1959–1966.
Farias M.L. Hypercalcemia of malignancy: clinical features, diagnosis and treatment. Arq Bras. Endocrinol. Metabol. 2005; 49: 816–824.
Papadopolou E.C., Batzios S.P., Dimitriadou M., Perifanis V., Garipidou V. Multiple myeloma and bone disease: pathogenesis and current therapeutic approaches. Hippokratia 2010; 14: 76–81.
Oyajobi B.O. Multiple myeloma/hypercalcemia. Arthritis Res. Ther. 2007; 9 (suppl 1): S4.
Roodman G.D. Pathogenesis of myeloma bone disease. Leukemia 2009; 23: 435–441.
Wawrocka-Pawlak M., Pawlak W.Z. Hiperkalcemia w chorobie nowotworowej – patofizjologia, diagnostyka, leczenie. Współcz. Onkol. 2003; 7: 482–496.
Hjertner O., Torgersen M.L., Seidel C. i wsp. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood 1999; 94: 3883–3888.
Tricot G. New insights into role of microenvironment in multiple myeloma. Lancet 2000; 355(9200): 248–250.
Merlini G., Fitzpatrick L.A., Siris E.S. i wsp. A human myeloma immunoglobulin G binding four moles of calcium associated with asymptomatic hypercalcemia. J. Clin. Immunol. 1984; 4: 185–196.
Lyell V., Khatamzas E., Allai T. Severe hypercalcaemia and lymphoma in an HTLV-1 positive Jamaican woman: a case report. J. Med. Case Rep. 2007; 1: 56.
Shu S.T., Martin C.K., Thudi N.K., Dirksen W.P. Rosol T.J. Osteolytic bone resorption in adult T-cell leukemia/lymphoma. Leukemia and Lymphoma 2010; 51: 702–714.
Matsuoka M., Jeang K.T. Human T-Cell Leukemia Virus Type I at Age 25: A Progress Report. Cancer Res. 2005; 65: 4467.
Nosaka K., Miyamoto T., Sakai T., Mitsuya H., Suda T., Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor κB ligand on adult T-cell leukemia cells. Blood 2002; 99: 2634–2640.
Senba M., Kawai K., Mori N. Pathogenesis of metastatic calcification and acute pancreatitis in Adult T-Cell Leukemia under hypercalcemic state. Leuk. Res. Treatment 2012; 2012: 128617.
Kurosawa M., Iwasaki H. Megakaryoblastic transformation of polycythemia vera with hypercalcemia. Ann. Hematol. 2002; 81: 668–671.
Vinti H., Taillan B., Pesce A., Michiels J.F., Bayle J., Cassuto J.P. Megakaryoblastic transformation of essential thrombocythemia, hypercalcemia and lytic bone lesions. Acta Haematol. 1990; 83: 53.
Kounami S., Yoshiyama M., Nakayama K. i wsp. Severe hypercalcemia in a child with acute nonlymphocytic leukemia: the role of parathyroid hormone-related protein and proinflammatory cytokines. Acta Hematol. 2004; 112: 160–163.
Lips P. Hypervitaminosis A and fractures. N. Engl. J. Med. 2003; 348: 347–349.
Bennett M.T., Sirrs S., Yeung J.K., Smith C.A. Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole. Leuk. Lymphoma 2005; 46: 1829–1831.
Cordoba R., Ramirez E., Lei S.H. i wsp. Hypercalcemia due to an interaction of all-trans retinoic acid (ATRA) and itraconazole therapy for acute promyelocytic leukemia successfully treated with zoledronic acid. Eur. J. Clin. Pharmacol. 2008; 64: 1031–1032.
Nakahata T., Komiyama A. Hypercalcemia associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Leuk. Res. 1993; 17: 441–443.
Sharma N., Jain S., Kumari S., Varma S. Hypercalcaemia with radiographic abnormalities in chronic myeloid leukaemia. Postgrad. Med. J. 1998; 74: 301–303.
Kwak H.S., Sohn M.H., Lim S.T., Kwak J.Y., Yim C.Y. Technetium-99m MDP bone scintigraphic findings of hypercalcemia in accelerated phase of chronic myelogenous leukemia. J. Korean Med. Sci. 2000; 15: 598–600.
Noguchi M., Oshimi K. Extensive bone marrow necrosis and symptomatic hypercalcemia in B cell blastic transformation of chronic myeloid leukemia: report of a case and review of the literature. Acta Haematol. 2007; 118: 111–116.
Seymour J.F., Grill V., Martin T.J., Lee N., Firkin F. Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein. Leukemia 1993; 7: 1672–1675.
Majumdar G. Incidence and prognostic significance of hypercalcaemia in B-cell non-Hodgkin's lymphoma. J. Clin. Pathol. 2002; 55: 637–638.
Seymour J. F., Gagel R. F. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993; 82: 1383–1394.
Matsuhashi Y., Tasaka T., Uehara E. i wsp. Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis. Leuk. Lymphoma 2004; 45: 397–400.
Laforga J.B., Vierna J. Aranda F. I. Hypercalcaemia in Hodgkin's disease related to prostaglandin synthesis. J. Clin. Pathol. 1994; 47: 567–568.
Ghazi A.A., Attarian H., Attarian S. i wsp. Hypercalcemia and huge splenomegaly presenting in an elderly patient with B-cell non-Hodgkin's lymphoma: a case report. J. Med. Case Reports 2010; 4: 330.
Burney I.A., Nirmala V., Al- Moundhri M.S., Woodhouse N.J. Nodular lymphocyte predominant Hodgkin’s lymphoma presenting as severe hypercalcaemia: a case report. Sultan Qaboos Univ. Med. J. 2007; 7: 247–251.
Littlewood T.J., Lydon A.P., Barton C.J. Hypercalcemia and osteolytic lesions associated with chronic lymphatic leukemia (CLL). J. Clin. Pathol. 1990; 43: 877.
Macintyre E.A. Hypercalcaemia in chronic lymphatic leukaemia. Postgrad. Med. J. 1986; 62: 393–394.
McMillan P., Mundy G., Mayer P. Hypercalcaemia and osteolytic bone lesions in chronic lymphocytic leukaemia. Br. Med. J. 1980; 25; 281: 1107.
Beaudreuil J., Lortholary O., Martin A. i wsp. Hypercalcemia may indicate Richter’s syndrome. Am. Cancer 1997; 6: 1211–1215.
Soni P.N. Hypercalcaemia and multiple osteolytic lesions in childhood acute lymphoblastic leukaemia. Postgrad. Med. J. 1993; 69: 483–485.
Laffan M.A., Talavera J.G., Catovsky D. Hypercalcaemia in T cell acute lymphoblastic leukaemia: report of two cases. J. Clin. Pathol. 1986; 39: 1143–1146.
Makras P., Papapoulos S. Medical treatment of hypercalcaemia. Hormones 2009; 8: 83–95.
Kovacs C.S., MacDonald S.M., Chik C.L., Bruera E. Hypercalcemia of malignancy in the palliative care patient: a treatment strategy. J. Pain. Symptom. Manage 1995; 10: 224–232.
Lumachi F., Brunello A., Roma A. Medical treatment of malignancy-associated hypercalcemia. Curr. Med. Chem. 2008; 15: 415–421.
Czyż J. Warzocha K. Szpiczak plazmocytowy – zasady postępowania w Instytucie Hematologii i Transplantologii. Hematologia 2012; 3: 255–266.
Tamburelli F.C., Proietti L., Scaramuzzo L., De Stefano V., Logroscino1 C.A. Bisphosphonate therapy in multiple myeloma in preventing vertebral collapses: preliminary report. Eur. Spine J. 2012; 21(Suppl 1): 141–145.
Pozzi S., Raje N. The Role of bisphosphonates in multiple myeloma: mechanisms, side effects, and the future. Oncologist 2011; 16: 651–662.
Ralston S.H., Coleman R., Fraser W.D. i wsp. Medical management of hypercalcemia. Calcif Tissue Int. 2004; 74: 1–11.
Bilezikian J.P. Management of acute hypercalcemia. N. Engl. J. Med. 1992; 326: 1196–1203.
Garcia-Gomez A., Ocio E.M., Crusoe E. i wsp. Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. PLoS One 2012; 7: e34914.
Body J., Facon T., Coleman R. i wsp. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 2006; 12: 1221–1228.
Lacy M.Q., Alsina M., Fonseca R. Pharmacokinetic and pharmacodynamic study of the antiinsulinlike growth factor type 1 receptor monoclonal antibody in patients with multiple myeloma. J. Clin. Oncol. 2008; 26: 3196–3203.